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Physiological Functions and Pathological Effects of Microglia

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (20 April 2026) | Viewed by 19694

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Special Issue Editor

Prof. Dr. Hiroshi Nakanishi

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Department of Pharmacology, Faculty of Pharmacy, Yasuda Women’s University, Yasuhigashi, Hiroshima 731-0153, Japan
Interests: microglia; brain inflammation; cathepsins; Alzheimer's disease; porphyromonas gingivalis
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Special Issue Information

Dear Colleagues,

Microglia comprise a variety of subsets with multiple roles in the healthy and diseased brain. Microglia engulf dendritic spines and prune connections between neurons to establish mature patterns of connection during postnatal development. On the other hand, a fault in synaptic elimination and disturbance of the microglial circadian clock system are accepted characteristic abnormalities in neuropsychiatric disorders, including autism. Furthermore, excessive inflammatory and immune responses mediated by pathological microglia are involved in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease. Therefore, in this Special Issue, we aim to retrieve the bank of data on physiological functions and pathological effects of microglia, which may aid in gaining a better understanding of their emergent properties in the brain.

Prof. Dr. Hiroshi Nakanishi
Guest Editor

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Keywords

circadian clock
homeostasis
immune response
microglia
neurodegenerative diseases
neuroinflammation
neuropsychiatric disorders
neuromodulation
phagocytosis
synaptic pruning

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Published Papers (7 papers)

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Research

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21 pages, 2903 KB

Open AccessArticle

TLC-Derived High-Polar Fractions of Celastrus paniculatus Seeds Attenuate Astrocyte-Driven Microglial Activation Through Suppression of CD40/iNOS Signaling and Pro-Inflammatory Cytokines

by Tanida Treerattanakulporn, Narongrit Thongon and Siriporn Chamniansawat

Int. J. Mol. Sci. 2026, 27(8), 3551; https://doi.org/10.3390/ijms27083551 - 16 Apr 2026

Viewed by 277

Abstract

Neuroinflammation mediated by astrocyte–microglia interactions plays a critical role in the progression of neurodegenerative disorders. Celastrus paniculatus (CP) seeds have long been associated with cognitive benefits; however, the chemical composition and anti-inflammatory potential of their high-polarity fractions remain poorly characterized. In this study, thin-layer chromatography (TLC)-derived high-polarity fractions (F6 and F7) from CP seeds were analyzed using untargeted LC–MS/MS metabolite profiling. After quality filtering, 99 metabolites were retained for classification, with enrichment of alkaloids and terpenoid-related compounds, including 41 structurally complex metabolites. To evaluate biological relevance, BV2 microglia were exposed to astrocyte-conditioned medium derived from H₂O₂-treated astrocytes (ACM-H), modeling sterile inflammatory signaling. ACM-H stimulation induced microglial activation characterized by morphological transformation, increased CD40 and inducible nitric oxide synthase (iNOS) expression, and elevated production of pro-inflammatory cytokines TNF-α and IL-6. Co-treatment with CP fractions attenuated ACM-H-induced inflammatory responses, with fraction F7 showing stronger effects than F6. Fraction F7 showed stronger inhibitory effects on CD40 and iNOS expression, suppressed TNF-α and IL-6 production, and partially restored ramified microglial morphology, whereas F6 exhibited comparable anti-inflammatory activity and showed a stronger effect on microglial phagocytic responses. Metabolomic analysis further indicated a higher relative abundance of terpenoid-related metabolites in F7. Collectively, these findings indicate that CP seed fractions, particularly F7, attenuate astrocyte-driven microglial activation in an in vitro sterile neuroinflammatory model. Full article

(This article belongs to the Special Issue Physiological Functions and Pathological Effects of Microglia)

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17 pages, 1385 KB

Open AccessArticle

Anti-Inflammatory and Antioxidant Properties of Bauhinia thailandica Leaf Extract in Microglial Cells

by Wilawan Promprom, Wannachai Chatan, Kritsana Homwutthiwong, Kwanjit Apaijit, Poonlarp Cheepsunthorn and Nootchanat Mairuae

Int. J. Mol. Sci. 2026, 27(6), 2809; https://doi.org/10.3390/ijms27062809 - 20 Mar 2026

Viewed by 551

Abstract

Neuroinflammation is pivotal in the development of numerous neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). Microglial cells, the principal immune cells of the central nervous system (CNS), are essential mediators of this process. Upon exposure to pathogenic stimuli such as lipopolysaccharide (LPS), microglia activate and release pro-inflammatory mediators, leading to heightened oxidative stress and neuronal damage. Therefore, targeting microglial activation is a promising therapeutic approach to prevent or slow neurodegeneration. This study aimed to investigate the antioxidant and anti-inflammatory effects of the leaf extract of the newly identified species Bauhinia thailandica on LPS-activated BV2 microglia. The phytochemical compound of the B. thailandica leaf extract was also investigated. BV2 cells were treated with LPS (1 μg/mL) for 24 h in the presence or absence of B. thailandica leaf extract (12.5 and 25 µg/mL). The levels of reactive oxygen species (ROS), nitric oxide (NO), and interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-alpha (TNF-α) were quantified with CM-H2DCFDA, Griess reagent assay, and ELISA, respectively. Treatment with LPS resulted in significant increases in ROS, NO, IL-6, IL-1, and TNF levels compared to untreated cells (p < 0.01). However, co-treatment with B. thailandica leaf extract significantly suppressed the production of these inflammatory markers (p < 0.01 for 25 µg/mL across all parameters, except TNF-α; p < 0.05). The results also showed that B. thailandica leaf extract possessed significant levels of total phenolic content (TPC; 70.55 mg GAE/g dry extract), total flavonoid content (TFC; 249.47 mg QE/g dry extract), and tannins (397.50 mg TAE/g dry extract). Phytochemical screening also revealed the presence of saponins and cardiac glycosides in the extract. In conclusion, the leaf extract of B. thailandica is a potent source of phytochemicals exhibiting antioxidant capabilities and has shown both antioxidant and anti-inflammatory actions in LPS-activated BV2 microglial cells. The findings indicate that B. thailandica leaf extract shows significant promise as a novel herbal treatment for neuroinflammatory disorders mediated by microglia. Further research is necessary to clarify the underlying mechanisms of action and to investigate the active substances responsible for these effects. Full article

(This article belongs to the Special Issue Physiological Functions and Pathological Effects of Microglia)

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23 pages, 5387 KB

Open AccessArticle

Tabernanthalog, a Non-Hallucinogenic Psychedelic, Alleviates Cancer-Induced Cognitive Deficits via Serotonergic Pathways

by Masahide Arinaga, Jun Yamada, Shoichiro Maeda, Ayumi Okamura, Yuto Oshima, Liye Zhang, Yiying Han, Kyoko M. Iinuma and Shozo Jinno

Int. J. Mol. Sci. 2025, 26(15), 7519; https://doi.org/10.3390/ijms26157519 - 4 Aug 2025

Cited by 2 | Viewed by 5716

Abstract

Cancer-related cognitive impairment (CRCI)—encompassing anxiety, depression, and memory deficits—significantly diminishes the quality of life in patients with cancer, yet remains underrecognized in clinical practice. In this study, we investigated the therapeutic potential of tabernanthalog (TBG), a non-hallucinogenic analog of psychedelic compounds, as a novel intervention for CRCI using a Lewis lung carcinoma (3LL) mouse model. Behavioral assessments revealed heightened anxiety-like behavior and memory impairment following 3LL cell transplantation. Biochemical analysis revealed reduced tryptophan levels in both blood and hippocampal tissue, accompanied by the downregulation of serotonergic receptor genes and upregulation of pro-inflammatory cytokine genes in the hippocampus of tumor-bearing mice. Additionally, microglial density and morphological activation were markedly elevated. TBG treatment reversed these behavioral deficits, improving both anxiety-related behavior and memory performance. These effects were associated with the normalization of microglial density and morphology, as well as the restoration of serotonergic receptor and cytokine gene expression. In vitro, TBG partially suppressed neuroinflammatory gene expression in BV-2 microglial cells exposed to conditioned medium from 3LL cells. Collectively, these findings suggest that TBG alleviates CRCI-like symptoms by modulating neuroinflammation and microglial activation. This study highlights TBG as a promising therapeutic candidate for improving cognitive and emotional functioning in patients with cancer. Full article

(This article belongs to the Special Issue Physiological Functions and Pathological Effects of Microglia)

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21 pages, 3299 KB

Open AccessArticle

Cognitive and Affective Dysregulation in Neuropathic Pain: Associated Hippocampal Remodeling and Microglial Activation

by Anna Tyrtyshnaia, Igor Manzhulo, Anastasia Egoraeva and Darya Ivashkevich

Int. J. Mol. Sci. 2025, 26(13), 6460; https://doi.org/10.3390/ijms26136460 - 4 Jul 2025

Cited by 6 | Viewed by 2502

Abstract

Neuropathic pain is a persistent and exhausting condition which results from damage to the nervous system and is often accompanied by emotional and cognitive impairments. In this study, we investigated dynamic changes in pain-related behaviors over 8 weeks using a spared nerve injury (SNI) model in male C57Bl/6 mice. We examined behavioral outcomes in conjunction with glial activation, neurogenesis, and glutamatergic signaling in the hippocampus to elucidate the mechanisms underlying cognitive and affective alterations associated with chronic pain. Our findings demonstrate that SNI-induced neuropathic pain progressively increases anxiety-like behavior and impairs both working and long-term memory. These behavioral deficits are accompanied by significant activation of microglia and astrocytes, a reduction in hippocampal neurogenesis, and a decrease in the expression of NMDA and AMPA glutamate receptor subunits and the scaffolding protein PSD-95. Taken together, our results suggest that hippocampal neuroinflammation and associated synaptic dysfunction contribute to the affective and cognitive disturbances observed in chronic pain, providing insight into potential molecular targets for therapeutic intervention. Full article

(This article belongs to the Special Issue Physiological Functions and Pathological Effects of Microglia)

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17 pages, 3942 KB

Open AccessArticle

Noradrenaline Synergistically Enhances Porphyromonas gingivalis LPS and OMV-Induced Interleukin-1β Production in BV-2 Microglia Through Differential Mechanisms

by Sakura Muramoto, Sachi Shimizu, Sumika Shirakawa, Honoka Ikeda, Sayaka Miyamoto, Misato Jo, Uzuki Takemori, Chiharu Morimoto, Zhou Wu, Hidetoshi Tozaki-Saitoh, Kosuke Oda, Erika Inoue, Saori Nonaka and Hiroshi Nakanishi

Int. J. Mol. Sci. 2025, 26(6), 2660; https://doi.org/10.3390/ijms26062660 - 15 Mar 2025

Cited by 5 | Viewed by 2497

Abstract

Infection with Porphyromonas gingivalis (Pg), which is a major periodontal pathogen, causes a large number of systemic diseases based on chronic inflammation such as diabetes and Alzheimer’s disease (AD). However, it is not yet fully understood how Pg can augment local systemic immune and inflammatory responses during progression of AD. There is a strong association between depression and elevated levels of inflammation. Noradrenaline (NA) is a key neurotransmitter that modulates microglial activation during stress conditions. In this study, we have thus investigated the regulatory mechanisms of NA on the production of interleukin-1β (IL-1β) by microglia following stimulation with Pg virulence factors, lipopolysaccharide (LPS), and outer membrane vesicles (OMVs). NA (30–1000 nM) significantly enhanced the mRNA level, promoter activity, and protein level of IL-1β up to 20-fold in BV-2 microglia following treatment with Pg LPS (10 μg/mL) and OMVs (150 μg of protein/mL) in a dose-dependent manner. Pharmacological studies have suggested that NA synergistically augments the responses induced by Pg LPS and OMVs through different mechanisms. AP-1 is activated by the β₂ adrenergic receptor (Aβ₂R)-mediated pathway. NF-κB, which is activated by the Pg LPS/toll-like receptor 2-mediated pathway, is required for the synergistic effect of NA on the Pg LPS-induced IL-1β production by BV-2 microglia. Co-immunoprecipitation combined with Western blotting and the structural models generated by AlphaFold2 suggested that cross-coupling of NF-κB p65 and AP-1 c-Fos transcription factors enhances the binding of NF-κB p65 to the IκB site, resulting in the synergistic augmentation of the IL-1β promoter activity. In contrast, OMVs were phagocytosed by BV-2 microglia and then activated the TLR9/p52/RelB-mediated pathway. The Aβ₂R/Epac-mediated pathway, which promotes phagosome maturation, may be responsible for the synergistic effect of NA on the OMV-induced production of IL-1β in BV-2 microglia. Our study provides the first evidence that NA synergistically enhances the production of IL-1β in response to Pg LPS and OMVs through distinct mechanisms. Full article

(This article belongs to the Special Issue Physiological Functions and Pathological Effects of Microglia)

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Review

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29 pages, 1367 KB

Open AccessReview

Microglia in Brain Aging and Age-Related Diseases: Friends or Foes?

by Kentaro Ishikawa, Risako Fujikawa, Kayoko Okita, Fumika Kimura, Takuya Watanabe, Shutaro Katsurabayashi and Katsunori Iwasaki

Int. J. Mol. Sci. 2025, 26(23), 11494; https://doi.org/10.3390/ijms262311494 - 27 Nov 2025

Cited by 2 | Viewed by 3088

Abstract

With the global rise in population aging, establishing effective strategies for the prevention and treatment of age-related neurodegenerative diseases, as well as their prodromal stage of cognitive frailty, has become an urgent challenge. Recent studies have revealed that the neural basis of both frailty and age-related disorders is closely associated with chronic neuroinflammation and impaired clearance of cellular debris, processes that are primarily regulated by microglia, the resident immune cells of the brain. As aging progresses, microglia exhibit reduced surveillance and motility, diminished phagocytic efficiency, and transition into a proinflammatory, hyperresponsive state. Such maladaptive microglia contribute to synaptic loss, white matter deterioration, and the spread of neurodegenerative pathology. Conversely, single-cell transcriptomic studies have identified distinct microglial subsets, including CD11c⁺ microglia, which show upregulation of lysosomal and lipid metabolism pathways, enhanced debris clearance, and elevated neurotrophic factor expression. These features suggest that certain microglial populations adopt protective or adaptive phenotypes that preserve neural integrity. However, under chronic inflammation or pathological conditions, even protective microglia may become inflammation-promoting. This review summarizes current evidence on microglial changes in aging, frailty, and neurodegeneration, emphasizing their dual roles and discussing strategies that modulate microglial function to maintain brain health and prevent or treat frailty and age-related diseases. Full article

(This article belongs to the Special Issue Physiological Functions and Pathological Effects of Microglia)

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21 pages, 1045 KB

Open AccessReview

Microglia/Macrophages in Autoimmune Demyelinating Encephalomyelitis (Multiple Sclerosis/Neuromyelitis Optica)

by Ryo Yamasaki

Int. J. Mol. Sci. 2025, 26(8), 3585; https://doi.org/10.3390/ijms26083585 - 10 Apr 2025

Cited by 4 | Viewed by 3955

Abstract

Microglia and macrophages are critical mediators of immune responses in the central nervous system. Their roles range from homeostatic maintenance to the pathogenesis of autoimmune demyelinating diseases such as multiple sclerosis and neuromyelitis optica spectrum disorder. This review explores the origins of microglia and macrophages, as well as their mechanisms of activation, interactions with other neural cells, and contributions to disease progression and repair processes. It also highlights the translational relevance of insights gained from animal models and the therapeutic potential of targeting microglial and macrophage activity in multiple sclerosis and neuromyelitis optica spectrum disorder. Full article

(This article belongs to the Special Issue Physiological Functions and Pathological Effects of Microglia)

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